Highly purified ethyl EPA and other EPA derivatives for psychiatric and neurological disorders

ABSTRACT

A pharmaceutical preparation comprising EPA in an appropriately assimilable form where of all the fatty acids present in the preparation at least 90%, and preferably at least 95%, is in the form of EPA and where less than 5%, and preferably less than 3%, is in the form of DHA is provided for the treatment of a psychiatric or central nervous disorder. The preparation may be administered with conventional drugs to treat psychiatric or central nervous disorders to improve their efficacy or reduce their side effects.

[0001] Even though many new drugs have been discovered over the pasttwenty years, psychiatric disorders are still relatively poorly treated.With most psychiatric illnesses, drug treatments do not treat allpatients successfully. This is true of schizophrenia, schizoaffectiveand schizotypal disorders, bipolar disorder (manic-depression), unipolardepression, dementias, panic attacks, anxiety, sleep disorders,attention, hyperactivity and conduct disorders, autism, personalitydisorders, and all other psychiatric conditions. For example, indepression, standard drugs achieve a 50% reduction in standarddepression scores in about two thirds of patients: the others do notrespond. In schizophrenia, the average improvements are only of theorder of 20-30% (S Leucht et al, Schizophrenia Research 1999;35:51-68)although individual patients may do much better than this.

[0002] The same is true of neurological disorders like Alzheimer'sdisease and other dementias, Parkinson's disease, multiple sclerosis,stroke, epilepsy and Huntington's disease. Again, many patients fail torespond to existing treatments, or respond only to a limited degree. Innone of these conditions do existing drugs reliably produce a completeremission of symptoms. There is therefore a great need for newtreatments, particularly ones which have novel mechanisms of action.

[0003] In PCT filing WO98/16216 attention was drawn to the value of aparticular fatty acid, eicosapentaenoic acid (EPA), and its derivatives,in the treatment of schizophrenia, depression and dementias. EPA is ahighly unsaturated fatty acid which can be derived from the dietaryessential fatty acid, α-linolenic acid by a series of three reactions(FIG. 1). EPA is a fatty acid containing 20 carbon atoms and 5 doublebonds, all in the cis-configuration. The double bonds are located at the5, 8, 11, 14 and 17 positions and the full chemical name is thereforeall cis (or all z) 5, 8, 11, 14, 17-eicosapentaenoic acid (or sometimesicosapentaenoic acid). The abbreviation which is always used is EPA. EPAis one of the highly unsaturated fatty acids, the main types of whichare shown in FIG. 2. The reactions which convert alpha-linolenic acid toEPA are slow in humans and only a very small proportion of dietaryα-linolenic acid is converted to EPA. EPA is also found in marinemicro-organisms and, via the food chain, makes up between 3% and 30% ofnatural marine oils derived from oily fish and marine mammals. EPA isfound linked to many different chemical structures. It can be found inthe form of phospholipids, tri, di- and monoglycerides, amides, estersof many different types, salts and other compounds. In each case the EPAmoiety can normally be split from the complex molecule to give the freeacid form which can then be linked again to other complex molecules.

[0004] As described in PCT filing WO 98/16216 it was unexpectedly foundthat an oil enriched in EPA was of value in treating schizophrenia,while an oil enriched in the closely related fatty acid, docosahexaenoicacid (DHA), was not. This was surprising because DHA is found in largeamounts in human brain whereas EPA is found only in trace quantities. Itwas therefore anticipated that DHA would be effective but EPA would not.In fact the opposite was found. WO 98/16216 disclosed the use of EPA andits derivatives for the treatment of psychiatric disorders.

[0005] The present invention provides a pharmaceutical preparationcomprising EPA in an appropriately assimilable form where of all thefatty acids present in the preparation at least 90%, and preferably atleast 95%, is in the form of EPA and where less than 5%, and preferablyless than 3%, is in the form of docosahexaenoic acid. Such preparationsare for the treatment of any disorder except peripheral vascular diseaseand hyper-triglyceridaemia.

[0006] Preferably, among the other fatty acids present there are lessthan 5%, and preferably less than 3%, of each of AA or DPA-n-3,individually. The same preferably applies for any other fatty acidswhich might compete with the EPA.

[0007] It is preferred that the aggregate DHA, AA and/or DPA-n-3 contentis less than 10%, of the total fatty acids present, and preferably lessthan 5%.

[0008] The EPA may be in the form of ethyl-EPA, lithium EPA, mono-, di-or triglyceride EPA or any other ester or salt of EPA, or the free acidform of EPA. The EPA may also be in the form of a 2-substitutedderivative or other derivative which slows down its rate of oxidationbut does not otherwise change its biological action on psychiatric orbrain disorders to any substantial degree (N. Willumsen et al.,Biochimica Biophysica Acta, 1998, 1369: 193-203)

[0009] Such pharmaceutical preparations may be used for the treatment ofa psychiatric or central nervous system disorder, including:schizophrenia, schizoaffective disorder or a schizotypal disorder;depression or manic-depression (bipolar disorder); anxiety or panicdisorder or social phobia, or a sleep disorder or an attention deficit,conduct, hyperactivity or personality disorder; autism; Alzheimer'sdisease, vascular dementia or another dementia, including multi-infarctdementia, Lewy body disease and diseases attributable to priondisorders; Parkinson's disease, or other motor system disorder; multiplesclerosis; stroke; epilepsy; and Huntington's disease or any otherneuro-degenerative disorder.

[0010] The present invention further provides formulations for use inpsychiatric and neurological disorders in which a drug which actsprimarily on neurotransmitter metabolism or receptors is prepared forco-administration with a pharmaceutical preparation according to thefirst aspect of the invention, as well as pharmaceutical formulationscomprising a preparation according to the first aspect of the inventiontogether with a drug which acts primarily on neurotransmitter metabolismor receptors. The conventional drug may administered in conventionaldosage, and the EPA formulations according to the first aspect of theinvention administered to the patient separately. The conventional drugmay be combined with the EPA preparations of the first aspect of theinvention in a combination formulation, or the two may be provided inseparate individual formulations but in a combination pack.

[0011] The EPA-containing preparations of the present invention may beadministered with any drug known to have an effect on the treatment ofpsychiatric or central nervous system disorders to improve the efficacyof the drug or reduce its side effects.

[0012] Suitable drugs for co-administration with the EPA preparations ofthe first aspect of the invention are clozapine; and any one of theclass of typical or atypical neuroleptics, including chlorpromazine,haloperidol, risperidone, olanzapine, sertindole, ziprasidone, zotepineor amisulpiride. Others are mentioned below.

[0013] The present invention still further provides a method of treatingor preventing the side effects of a drug used in treating psychiatric orneurological disorders by administration of the drug and apharmaceutical preparation according to the first aspect of the presentinvention.

[0014] It is important in treatment of psychiatric disorders to use pureor nearly pure EPA and EPA derivatives. It is a surprising conclusionthat DHA and related fatty acids may not only be ineffective but mayactually reduce the efficacy of EPA and its derivatives.

[0015] Phospholipids are the main components of nerve cell membranes. Innerve cells the middle carbon atom of phospholipids, known as Sn2, isusually attached to a highly unsaturated fatty acid (HUFA) such as DHA,arachidonic acid (AA), and sometimes EPA. HUFAs are fatty acidscontaining 18-26 carbon atoms and three or more double bonds. When nervecells are activated, for example by dopamine or serotonin, the activityof a group of enzymes collectively known as phospholipase A₂ (PLA₂) isfrequently increased. PLA₂ releases the HUFA from the Sn2 position,giving a free molecule of HUFA and a molecule of what is known as alysophospholipid (LyPL) (a phospholipid without a fatty acid attached tothe Sn2 position) (FIG. 3). Both of these molecules can be highly activecell signalling agents themselves, and can change cell function in anumber of different ways. In addition, the HUFA can be converted toprostaglandins, leukotrienes, hydroxy acids and a whole range ofshort-lived molecules which regulate neuronal function. For example, oneof these molecules derived from arachidonic acid, leukotriene C4, seemsto be absolutely required for normal nerve cell growth and development(E Mayatepek and B Flock, Leukotriene C4-synthesis deficiency: a newinborn error of metabolism linked to a fatal developmental syndromeLancet 1998; 352: 1514-7).

[0016] If cell function is to be normal, it is important that thisactivation should be temporary and should be terminated by removing thefree HUFA and the LyPL. Otherwise membrane damage may result because theLyPL can be destructive. Furthermore the free HUFAs are easily oxidisedto highly active free radicals which can do great damage. There is anemerging consensus that such membrane damage is a fundamentalpathological basis for many neurodegenerative disorders, includingAlzheimer's disease and other dementias, Parkinson's disease, stroke,Huntington's disease, all types of ischaemic damage, and multiplesclerosis. A range of initiating causative factors may all cause damageby the same common route. Phospholipid breakdown to LyPLs and free HUFAsmay also be important in epilepsy.

[0017] The signal transduction processes involving HUFAs and LyPLs areterminated in most cases by a two sequence reaction. First, the HUFA islinked to coenzyme A by a group of enzymes known as fatty acid coenzymeA ligases (FACLs). These enzymes are also known as acyl-CoA synthetases.The HUFA-coenzyme A derivative is then linked to the LyPL by a group ofenzymes known as acyl CoA: lysophospholipid acyltransferases (ACLATs)which liberate coenzyme A in the process (A Yamashita et al,Acyltransferases and transacylases involved in fatty acid remodelling ofphospholipids and metabolism of bioactive lipids in mammalian cells. JBiochem 122: 1-16, 1997). This sequence thus removes from the nerve cellthe HUFAs and the LyPLs and brings to an end the events associated withsignal transduction, so preparing the neuron for the next stimulus (FIG.3).

[0018] There is now a substantial amount of evidence which demonstratesthat in the three major psychotic mental illnesses there is increasedactivity of one or more of the phospholipase group of enzymes andparticularly in one or more of the PLA₂ group. These three illnesses areschizophrenia, bipolar disorder and major depression: the threedisorders are often found together in the same families, and often haveoverlapping ranges of symptoms. It has long been thought that at leastpart of their biochemical basis is common to all three disorders and itis possible that the PLA₂ abnormality constitutes that common factor. Inschizophrenia, there are increasing circulating levels of PLA₂ in theblood. In bipolar disorder, lithium, which is the main establishedtreatment, has been shown to inhibit the activity of PLA₂. In majordepression, there is depletion of HUFAs of the n-3 series frommembranes, coupled with activation of inflammatory responses whichoccurs with enhanced activity of PLA₂. Each of those illnesses, however,involves more than one biochemical abnormality: while a PLA₂ or relatedphospholipase abnormality may be common to all three, the otherabnormalities are probably specific to each disease.

[0019] In schizophrenia, it has recently been discovered that there is asecond abnormality in the fatty acid cycle. This is a deficit infunction of FACL-4, the enzyme which links HUFAs to coenzyme A in humanbrain (Y Cao et al, Cloning, expression and chromosomal localization ofhuman long-chain fatty acid-CoA ligase 4 (FACL4) Genomics 1998; 49:327-330). It is known that there is a defect in the incorporation ofHUFAs into phospholipids in schizophrenia but the precise enzyme has notbeen known. However, FACL-4 is found in brain, is specific for HUFAs,and when absent produces both brain abnormalities and also minorphysical abnormalities such as a high arched palate which are typical ofpatients with schizophrenia (M Piccini et al, FACL-4, a new geneencoding long-chain acyl-CoA synthetase 4, is deleted in a family withAlport Syndrome, elliptocytosis and mental retardation. Genomics1998;47:350-358). It is the combined presence of both the enzymeabnormalities which produces the disease.

[0020] The second or other abnormalities in bipolar disorder and inmajor depression are not yet known. Another phospholipase, PLC, whichacts at the Sn3 position to liberate inositol phosphates anddiacylglycerol may be involved in bipolar disorder. Both of thesemolecules, like LyPL and HUFAs, are involved in cell signalling:overactivation of both PLC and PLA₂ is likely to be related to bipolardisorder.

[0021] In the neurodegenerative conditions there appears to be anuncontrolled activation of membrane degrading enzymes likephospholipases, coupled with increased formation of free radicalsassociated with the oxidation of HUFAs and the membrane damage producedby LyPL. This type of phenomenon, with membrane damage associated withexcess phospholipase activity, has been well described by manyinvestigators in Alzheimer's disease and other dementias, in multiplesclerosis, in stroke and other brain disorders caused by ischaemia orinjury, in Parkinson's disease, in epilepsy and in Huntington's disease.In attention deficit disorder, also known as hyperactivity, there aredeficits in the blood of the highly unsaturated fatty acids which can beacted upon by phospholipases.

[0022] In all of these situations, therefore, there is some evidence ofincreased phospholipase activity and signal transduction activity whichmay not be terminated in a normal way. Thus the phospholipases, FACLsand acyl-transferases present new targets for drug action. Ourobservation that EPA-enriched materials are beneficial in psychiatricdisorders may therefore be explained in several ways:

[0023] EPA is known to inhibit phospholipase A₂ (M J Finnen & C RLovell, Biochem Soc Transactions, 1991;19:915) and so will help to downregulate the initial activation process. Interestingly, in this assaysystem, the related fatty acid docosahexaenoic acid (DHA) had no effect.

[0024] EPA has an unusually high affinity for the human brain enzymeFACL-4 (Y Cao et al, 1998 see above). Usually with enzymes which act onHUFAs, the activities with HUFAs like EPA, DHA and AA are similar, orvery frequently, DHA and AA are more active than EPA. With FACL-4,however, activity for AA was more than twice as great as for DHA,whereas that for EPA was 50% greater than for AA (Y Cao et al, 1998).This means that EPA will more readily than other HUFAs enter the cycle,form an EPA-CoA derivative, link to LyPL and so terminate the activityof free LyPL. Thus EPA will, more effectively than other HUFAs, stop theactivation once it has started.

[0025] Because EPA will compete with AA for incorporation into the Sn2position of phospholipids, EPA will also reduce the amount of AAincorporated into that position. This is likely to be particularlyimportant in depression, where AA levels are relatively or absolutelyabnormally high.

[0026] EPA itself is a HUFA which can be converted to desirablecompounds like prostaglandin I₃, (PGI₃) and prostaglandin E₃ (PGE₃)which have a range of anti-inflammatory and antithrombotic actions whichmay be particularly useful in neurodegenerative disorders and indepression. The compounds derived from EPA appear to be less potentiallyharmful than the equivalent compounds derived from AA. Replacement of AAby EPA is therefore likely to be of particular value in all theneurodegenerative disorders described above, where at least part of thedamage is attributable to overactive phospholipases which release AAwhich can then be converted to pro-inflammatory compounds.

[0027] The purification of EPA is difficult and complex. Because itsfive double bonds must all be in the right positions in the carbon chainand must all be in the cis configuration, EPA is difficult tosynthesize. In nature EPA is almost always found mixed with other fattyacids in the forms of triglycerides and phospholipids. The principles ofpurification of EPA are well known to those skilled in the art andinclude low temperature crystallisation, urea fractionation, lithiumcrystallisation, fractional distillation, high pressure liquidchromatography, supercritical carbon dioxide chromatography and variousother forms of chromatography using silica gels and other columnpackings. The application of these known techniques has been difficultto apply in practice on a large scale and only recently has pure EPA(more than 90% pure and preferably more than 95% pure) become availablefor testing in psychiatric and CNS disorders. In one version of thepurification process, natural fish oil triglycerides rich in EPA aresaponified and the fatty acids converted to the ethyl ester form. Apreparation enriched in ethyl EPA is then prepared by moleculardistillation with collection of the appropriate fraction. This fractionis then converted to a preparation containing over 80% of ethyl EPA byurea precipitation. The final preparation of more than 96% pure ethylEPA is then achieved by either silica gel chromatography or highpressure liquid chromatography.

[0028] Conventionally, most studies on the uses of EPA and related fattyacids have used materials partially enriched in EPA but also containingsubstantial amounts of other fatty acids, especially docosahexaenoicacid (DHA) which is found alongside EPA in most natural oils. The fattyacids have usually been in the triglyceride or ethyl ester forms, andoccasionally in the free acid and phospholipid forms. Docosapentaenoicacid (DPA n-3) is also a common component of such materials. The newunderstanding of possible mechanisms of action of EPA which we havedeveloped has, however, led to the realisation that the purer is the EPAthe better is likely to be the activity. This is not just a question ofdose, although that is indeed a valuable aspect of the application ofpure EPA. From the point of view of a patient, particularly a mentallydisturbed patient, it is obviously better to give, say, 1 g of EPA as a95% pure preparation than, say, 5 g of a 19% pure preparation providingthe same total amount of EPA. The patient is much more likely to complywith the lower volumes required with the highly purified compound.

[0029] More importantly, other fatty acids such as AA, DPAn-3, and DHA,which are relatively similar in structure to EPA, but do not share thesame spectrum of biological activity, compete with EPA for binding tothe active sites of all the relevant enzymes. Thus these other fattyacids will compete with EPA for occupation of these active sites andreduce its activity. The purer the preparation of EPA the more likely isit to occupy the relevant active binding sites, and the more likely isit to be able to have desirable biological effects.

[0030] Our attention was unexpectedly drawn to the importance of highlypurified EPA by our experience with a patient, a depressed women aged 35years. She had had a long history of depression with Hamilton DepressionRating Scale scores ranging from 15 to 25. Trials of several differentantidepressants, including traditional tricyclic compounds and newerselective serotonin reuptake inhibitors had failed to have an impact.Because of evidence of the importance of EPA in depression she was givena three months trial of 4 g/day of an EPA enriched fish oil containing25% of EPA, together with 8% of DHA and 10% of other highly unsaturatedfatty acids. At the start of this trial she had a Hamilton score in the20-22 range and at the end a Hamilton score in the 16-18 range, a smallbut not very important improvement. She continued the EPA-rich oil for afurther two months without any further change. A 96% pure preparation ofethyl-EPA with less than 3% DHA then became available to me and it wassuggested that the woman should switch from taking 4 g/day of the 25%EPA preparation to 1 g/day of the 96% preparation. We expected that thiswould be more convenient but did not expect any clinical improvementbecause the EPA daily dose remained unchanged. However, surprisingly,after about 3-4 weeks she began to experience a major improvement withHamilton scores falling below 6 for the first time for several years. Asa result of this, and of thinking about the evidence relating to thebinding of EPA to FACL-4 and presumably to other proteins, we came tothe conclusion that it was important for clinical efficacy to administerEPA in a highly purified form for maximum clinical effectiveness.Surprisingly, the same daily dose of EPA in a purified form seemsconsiderably more effective than that dose when mixed with other fattyacids which may compete with EPA for binding to the relevant sites ofaction.

[0031] This initial experience has now been confirmed by many other casereports in a range of psychiatric disorders. Some examples of theobservations made include the following:

[0032] Schizophrenia: A patient with a ten-year history had been wellcontrolled by taking 16×0.5 g capsules a day of fish oil containing 24%of EPA and 8% of DHA. This provided around 1.9 g/day of EPA and 0.6g/day of DHA. He was not taking other antipsychotic drugs. However, hedid not like taking the high doses of fish oils and tried to reduce thedose. However, when he did this the symptoms returned and it wasconcluded that he had to take around 2 g/day of EPA to remain well. Whenthe purified ethyl-EPA became available, he was switched to 4×0.5 gcapsules, also providing around 2 g/day. This controlled his symptomsvery well. He therefore dropped the dose to 1 g/day. Unlike the previoussituation with the mixed fish oil providing 1.9 g/day of EPA and 0.6g/day of DHA, reducing the ethyl-EPA dose to 1 g/day did not lead to arecurrence of symptoms. 1 g/day in pure form therefore appeared aseffective and possibly more effective than 1.9 g per day of EPA whenmixed with DHA and other fatty acids.

[0033] Bipolar disorder: Bipolar disorder is a condition in which eithera depressive or a manic state is episodic, or in which depressive ormanic states alternate. The standard treatments are lithium or valproatederivatives, or the antipsychotic neuroleptic drugs which areparticularly used to control the manic states. Standard antidepressantsare sometimes used but they have to be applied with caution becausethere is a risk that they may precipitate a manic state.

[0034] Very high doses (9-10 g/day) of mixed EPA and DHA have beenreported to be helpful in managing bipolar patients, improvingdepression and reducing the risk of relapse into either a depressive ora manic episode (A Stoll et al, Omega-3 fatty acids in bipolar disorder.Archives of General Psychiatry, 1999; 56: 407-412). Prior to theavailability of the pure ethyl-EPA, five patients with bipolar disorder,whose condition was only partially controlled by lithium withintermittent neuroleptics to control the manic episodes, were given10-20 g/day of a fish oil containing 18% of EPA and 12% of DHA. Thisprovided 1.8-3.6 g of EPA and 1.2-2.4 g of DHA per day. On thistreatment the patients were less depressed, and less prone to moodswings, as indicated by following their clinical course for over a year.They were, however, far from completely normal. When the pure ethyl-EPAbecame available, they were switched from the fish oil to the pure EPAat a dose of 2 g/day in the form of four 0.5 g soft gelatin capsules. Ineach case their clinical condition improved considerably. Theirdepressions became substantially better and they showed less tendency tomood swing. In particular they all noted an improvement in somethingwhich is difficult to measure by conventional psychiatric rating scales.This is a sense of inner tension or dysphoria, a state which isassociated with the illness, but which may be exaggerated or changed byantipsychotic drugs to a state of confused tension, sometimes describedas a sense of the brain being replaced by cotton wool, and a difficultyof thinking clearly in a straight line. Remarkably, the patientsreported that this sense of dysphoria, tension and “cotton-woolthinking” was greatly reduced or disappeared altogether. They had notnoticed this effect which being treated with the higher dose of EPA inthe form of the EPA/DHA mix in fish oil. Thus again the purified EPA hada greater and qualitatively different effect from the mixed EPA and DHA,supporting the idea that DHA actually reduces the therapeutic effect ofEPA, and that highly purified EPA is therapeutically more effective.

[0035] Attention deficit hyperactivity disorder (ADHD): ADHD and closelyrelated conditions like attention deficit disorder and conduct disordersare commonly found in children. Occasionally they may be successfullytreated by behaviour modification and other psychological techniques orby careful attention to diet. However, in most cases, paradoxicaltreatment with one of the stimulant drugs related in their action toamphetamine is required. Methylphenidate and dextroamphetamine are thecommonest used. A seven year old boy with serious ADHD since infancy wasdriving his parents to distraction. Psychological measures and diet hadcompletely failed, and his condition was only partially controlled bymethylphenidate. The parents were concerned about the long termconsequences of stimulant drugs. The boy was therefore tried on twocapsules of pure ethyl-EPA per day. There was little change for thefirst two weeks but then a substantial improvement in behaviourdeveloped. The boy became less tense and irritable, less hyperactive,more open to reasoned discussion and enormously less disruptive both athome and school. Even when his methylphenidate was stopped, hisbehaviour remained improved.

[0036] Dementia: A 75 year old woman developed dementia, probably ofAlzheimer type but possibly with multi-infarct contributions because ofassociated cardiovascular disease. As often occurs she also becamewithdrawn and depressed but, unfortunately, this state was interruptedby irrational and violent outbursts, usually directed at members of herfamily, but also sometimes against complete strangers. She was tried ontwo cholinergic drugs: although these produced a small improvement inher cognitive state they did nothing for her depression, irritabilityand anger. She was tried on a dose of 4×0.5 g capsules of pureethyl-EPA, two given in the morning and two in the evening. Within fourweeks she had experienced a remarkable improvement, becoming morecheerful and friendly and showed a substantially reduced irritability.Her family also thought her cognition had improved but this is difficultto be certain of because of her improved mood.

[0037] Panic and anxiety disorders are very common. They are associatedwith panic attacks which may come out of the blue with no precipitatingfactors at all, or may be associated with mildly stressful situationswhich in normal people would evoke no such reactions. Thecharacteristics of panic attacks are a feeling of severe anxiety,difficulty in breathing, sweating, a feeling of abdominal discomfortknown as “butterflies in the stomach” and a feeling of legs collapsing.Very frequently associated with all these psychological symptoms, thereis also a tachycardia, which is associated with a subjective sensationof cardiac palpitations. Insomnia is common, and patients frequentlywake up spontaneously in the middle of the night with palpitations andpanic. Patients are also frequently depressed. Common treatments includeanti-anxiety drugs such as benzodiazepines, beta-blockers to control thepalpitations and anti-depressants.

[0038] We have now treated several patients who have panic and anxietydisorders with purified ethyl-EPA with excellent effect. Three casehistories follow. A 29 year old woman was disabled as a result offrequent and uncontrollable panic attacks and palpitations. Treatmentswith benzodiazepines, beta-blockers and antidepressants had proved onlypartially effective in controlling her symptoms. She was then given adose of 2 g per day of ethyl EPA as four 500 mg capsules. Her symptomsdramatically improved and over a period of three months her panicattacks and palpitations were almost absent, with only two relativelymild attacks. This treatment was much more effective than any previoustreatment she had received. A 56 year old woman had suffered from mildanxiety and panic attacks for most of her life but these had become muchworse over the previous few years in association with various problemswith her children. Anxiolytics and antidepressants had only modesteffects and her palpitations were uncontrolled even by relatively highdoses of beta-blockers. Again she was treated with ethyl-EPA over aperiod of four months. Her anxiety and panic attacks became much lesssevere, and even when they occurred were free of palpitations which hadpreviously worried her a great deal. The third patient was a 55 year oldhousewife who had been through two divorces and was now in a long-termrelationship. She had several panic attacks every week, sometimes in themiddle of the night, and always accompanied by strong palpitations whichwere very worrying for her. These panic attacks were accompanied bydepression. She was very reluctant to go out for fear of having anattack and this seriously disrupted her life. Again, antidepressants,beta-blockers and anxiolytics had had only limited beneficial effects.She was also treated with ethyl-EPA and over a period of four monthsexperienced a dramatic reduction in her panic attacks and palpitations.Sometimes, she felt that an attack of palpitations might be coming onbut it rarely materialised. As a result, she felt increasing confidenceand was able to resume a much more normal life. These observationsdemonstrate that purified ethyl-EPA is effective in the management ofpanic disorder.

[0039] Another use for ethyl-EPA is as an adjunct to the management ofsevere depression when using electroconvulsive therapy (ECT). ECT isused most other treatments have failed to be helpful. It involves theadministration of shocks under anaesthesia and, although effective, isused with reluctance by both patients and doctors because of fears thatit may damage the brain and cause memory loss. Anything from five totwenty or even more shocks may be given during a course of treatment. Itwould be highly desirable to be able to limit the numbers of shocksrequired to achieve a beneficial effect and in a small number ofpatients we have found that this is indeed the case.

[0040] These observations indicate that pure ethyl-EPA is of value in awide range of psychiatric and neurological disorders, reflecting thecommon involvement of membrane and phospholipid abnormalities in theseconditions.

[0041] But E-EPA is not only useful as a therapy by itself. E-EPA can beco-administered with standard drugs used in various psychiatric andneurological conditions and can substantially enhance the response tostandard therapy, and also reduce many of the side effects of standardtherapy. The present invention provides combination therapy involvingthe co-administration of E-EPA with standard drugs, either involving thesame formulation or the same packaging.

[0042] Our attention was drawn to this possibility by a striking casehistory. A middle aged male patient with a long history of schizophreniahad failed to respond to therapy with “typical” neuroleptics. “Typical”neuroleptics are drugs with a strong blocking action on dopamine D₂receptors (B Leonard, Fundamentals of Psychopharmacology, 2^(nd)edition, Wiley, New York, 1997). This mechanism is thought to beresponsible for their rapid effects on the so-called “positive” symptomsof schizophrenia (such as hallucinations, delusions and thoughtdisorder). These drugs, however, have little effects on the so-called“negative” symptoms of schizophrenia such as anhedonia, lack of affect,and emotional and social withdrawal. The D₂ blocking action is alsoresponsible for many of the adverse effects of these drugs, whichinclude extrapyramidal movement disorders, excess prolactin secretionand tardive dyskinesias. Examples of widely used drugs in this classinclude chlorpromazine, thioridazine, haloperidol, pimozide,flupenthixol and sulpiride.

[0043] In spite of treatment with full doses of several of these drugsthe patient failed to respond. He was therefore put on the first of theso-called “atypical” neuroleptics, clozapine. These atypical drugs havea much lower affinity for D₂ receptors, and often have a wide range ofother receptor actions. These may include blockade of one or more of theother dopamine receptors such as D₁, D₃ or D₄, and also usuallyincluding blockade of one or more classes of serotonin receptors. Theydo not cause much prolactin secretion and rarely cause extrapyramidalmovement disorders. They may also have actions at other receptors,including histamine, glutamate and acetyl choline receptors. Drugs inthis class include clozapine, olanzapine, quetiapine, risperidone,ziprasidone, sertindole and perhaps zotepine and amisulpiride. There aremany drugs of this type in early development, all characterised by alower affinity for D₂ receptors than the “typical” neuroleptics.

[0044] The patient was treated with clozapine, eventually reaching amaximum dose of 900 mg/day. This produced some improvement but thepatient remained severely ill. He was tense, withdrawn and suspiciousand exhibited bizarre behaviour. For example, he refused to allow anysound when he turned on the television set because of his paranoia aboutpeople speaking to him. This was naturally irritating to anyoneattempting to watch television with him. The patient was given trials ofolanzapine, quetiapine and risperidone with no substantial benefit.Clinically he appeared to do best on clozapine and so was maintained formany months on 900 mg/day. The main side effect of clozapine whichbothered him was the hypersalivation.

[0045] E-EPA in a dose of 2 g/day was then administered in addition toclozapine. Although EPA is an effective treatment for schizophrenia, itsonset of action is slow and substantial benefits are not normally seenuntil 4-8 weeks after starting treatment (B Puri et al, Sustainedremission of positive and negative symptoms of schizophrenia followingtreatment with eicosapentaenoic acid, Archives of General Psychiatry55:188-189, 1998). However, in this clozapine-treated patient who hadbeen so seriously ill for many years, the effects began to be apparentwithin days and were dramatic within two weeks. They were noted both bythe patient himself and by family and friends. In particular, instead ofbeing depressed he became cheerful, instead of being tense he becamerelaxed, instead of being withdrawn and refusing to speak, he becomeoutgoing and chatty. For his family and friends, one of the first andmost striking effects was that he allowed the television to be on with anormal sound level. The psychiatrist in charge of the patient noted “Icannot remember ever seeing such a dramatic improvement in aschizophrenic illness in less than 2 weeks”. A particularly importantaspect of this case is that the clozapine-induced hypersalivation wasconsiderably reduced.

[0046] In this patient, clozapine and other neuroleptics, both typicaland atypical, clearly had very limited beneficial effects. On the otherhand E-EPA had a surprisingly large and unexpectedly rapid effect whichis not normally seen if E-EPA is administered alone. This suggests astrong beneficial interaction between clozapine and E-EPA and suggeststhat clozapine and E-EPA should be administered together in at leastsome patients.

[0047] There are good reasons why E-EPA should have additive and evensynergistic effects in association with conventional psychotropic drugs,not only for schizophrenia but also for all other psychiatric andneurological disorders. This is because most drugs used for themanagement of psychiatric and neurological disorders act onneurotransmitter metabolism or on neurotransmitter receptors, modulatingthe synthesis, inactivation, reuptake or responses to neurotransmitterssuch as noradrenaline, serotonin, dopamine, glutamate, acetyl choline,and gamma-aminobutyric acid (GABA). However, many phenomena in nervecells occur after a receptor has been occupied by a neurotransmitter orblocking agent. Receptor occupation leads to many changes in cellularfunction which go under the general name of “signal transduction” or“cell signalling” and which include changes in G proteins, in calciummovements, in sodium and potassium movements, in metabolism ofphospholipids and eicosanoids, in cyclic nucleotide changes, and in generegulation. These are only some examples, of the processes which takeplace under the general heading of signal transduction. The specificexample of activation of the PLA₂ cycle which may follow activation ofdopamine, serotonin, acetyl choline or glutamate receptors is shown inFIG. 3.

[0048] There is increasing evidence that some of the abnormalities whichcause psychiatric and neurological disorders are not at theneurotransmitter or receptor level but are at the post-receptor signaltransduction level. Much of this evidence in relation to psychiatricdisorders has been summarised in a recently published book (PhospholipidSpectrum Disorder in Psychiatry, ed. M Peet, I Glen & D F Horrobin,Marius Press, Carnforth, UK, 1999). If this is so, then drugs like mostof these currently in use, which act at the neurotransmitter or receptorlevel, will only have limited efficacy. This is true of drugs for manytypes of psychiatric and neurological disorders, most of which havetheir primary actions at the neurotransmitter or receptor level.Diseases currently treated by drugs affecting neurotransmittermetabolism or neurotransmitter receptors include schizophrenia,depression, bipolar disorder, attention deficit, conduct and relateddisorders, Parkinson's disease, dementias, anxiety, panic and socialphobic disorders, and premenstrual syndrome. The current drugs would beexpected to have additive or synergistic effects with drugs which act atthe post-receptor signal transduction level, since then the drugcombination would be acting at two different levels in the neuron.

[0049] The main effect of E-EPA is to modulate post-receptorphospholipid-related signal transduction. Indirectly these actions thenmodulate other processes or enzymes such as protein kinases, calciummovements, cyclic nucleotide metabolism or gene expression. There aretherefore strong and potentially valuable interactions between EPA andany of these other classes of drug.

[0050] This case history of the single patient has unexpectedly drawnour attention to a general principle, namely the idea that E-EPA orindeed any other form of biologically active EPA may be usefullyco-administered with any psychotropic or neurological drug whichprimarily acts on neurotransmitter metabolism or neurotransmitterreceptors.

[0051] The drugs which may usefully be co-administered with EPA includetypical and atypical antischizophrenic drugs, antidepressants of allclasses, drugs used in control of anxiety or panic, drugs used toregulate sleep, and drugs used in the management of Parkinson's diseaseor dementia. All these drugs act primarily at the level ofneurotransmitters or their receptors.

[0052] The general principle that E-EPA can potentiate the effects ofstandard drug treatments can be illustrated by further case histories. A50 year old man who suffered from severe depression had been tried onseveral antidepressants without effect. Eventually he was treated with aselective serotonin reuptake inhibitor (SSRI) called citalopram which,surprisingly, relieved some of his depression even though other SSRIshad failed. This produced an improvement which was sustained for severalmonths although during this time he continued to be moderatelydepressed. In addition to citalopram he was then given 1 g/day ofethyl-EPA. After four weeks, for the first time in several years, heexperienced a lightening of mood and regained much of the interest inlife which he thought he had lost forever. Another case was a youngwoman of 21 who dropped out of college with a schizophrenic breakdown.She experienced auditory hallucinations which kept telling her that oneof her professors was out to destroy her college career, she becametotally distrustful about her close student friends, and she produced abizarre series of assignment essays which illustrated severe thoughtdisorder. She was treated with 10 mg/day olanzapine which stopped thehallucinations, reduced the paranoia and thought disorder but, sheclaimed, made her dysphoric and “fuzzy” and unable to think clearly. Italso made her very sleepy, and gave her a large appetite causing her toput on weight. She was given 2 g/day ethyl-EPA and after about 4 weeksclaimed to be thinking more clearly, and to have a reduced appetiteallowing her to lose weight. After a year she was able to return tocollege where again she consistently performed at the A and B gradelevel.

[0053] A 40 year old man had become ill with schizophrenia at the age of25. He had florid hallucinations and paranoia, but also withdrew himselffrom most of his friendships and lived alone. He was tried on variousdrugs, some of which produced side effects which he did not like.Eventually a dose of the typical neuroleptic, haloperidol, was foundwhich stopped most of the hallucinations and kept his paranoia withinreasonable bounds, but seemed to make him even more withdrawn. He livedalone, ceased to communicate with most of his friends, and went aroundto town alone and muttering to himself. His psychiatrist heard aboutethyl-EPA and decided to try it in addition to the standard drug. Aftereight weeks on treatment with 4 g/day his outlook was transformed. Hisresidual hallucinations disappeared and he became emotionally muchwarmer and more friendly. He was even persuaded to go on holiday withhis family where he enjoyed himself and made new friends. The EPAtherefore reversed the extreme withdrawal which appeared to have beenexaggerated by haloperidol.

[0054] The typical neuroleptics in some patients produce a distressingcondition called tardive dyskinesia. This is due in part to irreversiblechanges in the brain since the condition often does not remit if drugtreatment is stopped. The patient experiences uncontrollable twitchingand other movements. These can affect any part of the body but commonlyaffect the face where they are particularly distressing. Facial twitchesand movements, including protrusions and uncontrollable movements of thetongue occur. Several patients we have treated with EPA have experiencedsubstantial relief from tardive dyskinesia. Movements have becomesubstantially less and in some patients have disappeared completely.

[0055] Clozapine is regarded as a particularly effective drug by manypsychiatrists but it has a range of severe side effects. From thepatient's point of view one of the most troublesome is hypersalivation.This may not sound very serious but the constant flow of large volumesof saliva is in fact very distressing for the patient and for those whoare associated with the patient; The mechanism of the hypersalivation isunknown. Completely unexpectedly, in three clozapine-treated patientsfor whom hypersalivation was a major problem, treatment with ethyl-EPAnot only caused a substantial improvement in psychiatric state, but alsodramatically reduced the salivation to normal levels to the great reliefof the patients and their carers.

[0056] Obesity is another common side effect of antipsychotropic drugs.In this respect some of the newer drugs like olanzapine frequently seemto be even worse offenders than the typical neuroleptics. A young womanwho had had a schizophrenic breakdown in her early-twenties had beentreated with typical neuroleptics for about 10 years and then for thepast two years with olanzapine. She preferred the olanzapine but itstill left her withdrawn and unable to communicate normally with friendsor family. To her distress it caused her to put on over 10 kg in weight.Her doctor decided to test ethyl-EPA in addition to olanzapine. Over thenext six months her withdrawn state gradually improved and she began toperform again as a musician which she had not done for several years.Equally important for her self-esteem she lost most of the weight whichshe had gained when she first started on olanzapine.

[0057] These case histories clearly demonstrate the following:

[0058] 1. Pure ethyl-EPA has strong therapeutic effects in its own righton schizophrenia, bipolar disorder, depression, attention deficitdisorder and dementia. Like other drugs with antipsychotic actions it islikely to have some beneficial effects in most psychiatric disorders andalso in neurological disorders associated with membrane damage. Theseinclude the various types of dementia (including Alzheimer's disease,multi-infarct vascular dementia and Lewy body disease), multiplesclerosis, Parkinson's disease and Huntington's chorea.

[0059] 2. Pure ethyl-EPA enhances the beneficial effects of a wide rangeof psychiatric and neurological drugs. This makes a great deal of sensesince it is increasingly apparent that many abnormalities in psychiatryand neurology lie beyond the neurotransmitter receptor in the signaltransduction, systems of neurons and other cells. EPA acts on thesesignal transduction systems, providing a rational explanation for thepositive interactions between EPA and other drugs.

[0060] 3. Completely unexpected was the ability of EPA to reduce theadverse effects of psychiatric and neurological drugs. The mechanism isunknown but it appears to be a relatively general phenomenon as it hasbeen noted with drug-induced obesity, movement disorders, sedation,dysphoria and salivation.

[0061] Although the case reports of the effects of ethyl-EPA areconvincing and in some cases dramatic, unequivocal proof of its efficacymust come from randomised, placebo-controlled trials. We therefore setup a randomised, placebo-controlled study of EPA in 34 patients who hadschizophrenia according to the criteria set out in the AmericanPsychiatric Association's Diagnostic and Statistical Manual of MentalDisorders (4^(th) edition, DSM-IV). All of these patients were beingtreated with clozapine drugs but all remained seriously ill, withschizophrenic symptoms. Like many schizophrenics, some of the patientswere also depressed. All were assessed at baseline and after 12 weeksusing the Positive and Negative Symptom Scale for Schizophrenia (PANSS)and the Montgomery-Asberg Depression Rating Scale (MADRS).

[0062] After giving informed consent, all the patients were randomisedon a double blind basis to one of three groups: placebo, or 1 g or 2 gof ethyl-EPA per day in the form of 0.5 g capsules. Placebo and EPAcapsules were indistinguishable from one another in appearance.

[0063] The percentage changes from baseline in the four groups are shownin the table. All the patients improved to some degree so all thechanges are percentage improvements rating scale Placebo 1 g EPA 2 g EPATotal PANSS 5.2% 18.8% 17.1% positive PANSS 9.5% 20.0% 25.0% negativePANSS 11.1% 22.7% 22.7% MADRS 13.3% 35.7% 35.7%

[0064] As can be seen, on all the rating scales the EPA groups didsubstantially better than the placebo group. E-EPA (ethyl-EPA) waseffective in reducing symptoms of schizophrenia, symptoms of depressionand side effects of existing drugs. The simultaneous effect ondepression, as indicated by the MADRS scale, and schizophrenia, asindicated by the PANSS scale, is particularly important. These resultstherefore confirm the individual patient reports and demonstrateunequivocally that E-EPA has a strong therapeutic effect.

[0065] Of particular note is the fact that there were no reported sideeffects attributable to the E-EPA and no differences at all betweenplacebo and active treatment in the side effects which were reported.This means effectively that, in dramatic contrast to almost all otherdrugs used in psychiatry or neurology, EPA has no important side effectsat all.

[0066] Huntington's disease in many respects the most devastating of alldiseases which affect the brain. It is a dominantly inherited geneticdisorder which usually becomes manifest between the ages of 30 to 50 andleads to death after a course which usually lasts about 15-25 years.Half of the children of patients will also develop the disease (W JKoroshetz, pp. 654-661 in “Office Practice of Neurology, ed M A Samuels& S Feske, Churchill Livingstone, New York, 1996).

[0067] The affected gene is for a protein called huntingtin located onchromosome 4p16.3. The gene contains a polymorphic trinucleotide CAGrepeating area. In normal individuals the number of CAG repeats isusually less than 35, whereas in Huntington's disease the number ofrepeats is higher than this. The longer the number of repeats, theearlier the disease is likely to develop. The repeats result inoverexpression of huntingtin which forms aggregates in the affectedneurons. The aggregates may be associated with membranes and with thecytoskeleton and cause malfunction and eventually death of the neuronsconcerned. There can be damage to almost any part of the brain but it isparticularly evidence in the basal ganglia structures, the caudate andthe putamen.

[0068] Several other neurological diseases are now known to beassociated with excessive numbers of trinucleotide repeats in othergenes. It is believed that similar mechanisms of protein accumulationand neuronal damage may be involved (S T Warren, The expanding world oftrinucleotide repeats, Science 1996; 271:1374-1375: P Djion et al, Codenrepeats in genes associated with human diseases, Proceedings of theNational Academy of Sciences of the USA 1996; 93:417-421). In additionto Huntington's disease, the illnesses known to be caused in this wayinclude fragile X syndrome, Friedreich's ataxia, spinal and bulbarmuscular atrophy, spinocerebellar ataxia type I,dentato-rubral-pallidoluysian atrophy, Haw River syndrome,Machado-Joseph disease, and myotonic dystrophy.

[0069] Huntington's disease can manifest an extraordinary wide range ofsymptoms and signs (W J Koroshetz, 1996) and can exhibit features ofschizophrenia, depression, anxiety, irritability, loss of emotionalcontrol, epilepsy, Parkinson's disease and dementia. It has beensuggested that the fundamental end mechanism in a wide range ofneurological diseases, including Huntington's disease, amyotrophiclateral sclerosis, Parkinson's disease, Alzheimer's disease and otherdementias, and cerebellar degeneration is oxidative damage to membranesand to proteins (M F Beal, Aging, energy and oxidative stress inneurodegenerative diseases, Annals of Neurology 1995; 38: 357-366). Itis postulated that in these diseases, normal or abnormal proteinsaggregate and damage internal and external membranes. The differencesbetween the diseases relate to the nature of the proteins and to thesite of the neurons most affected, but the overall processes aresimilar.

[0070] In a typical patient with Huntington's disease, the illnessbeings with mild motor incoordination, forgetfulness, slowness toperform actions and emotional lability with irritability. Theincoordination then progresses to obvious neurological damage withsudden jerking movements, and repeated uncontrollable writhing andrestlessness, a pattern going under the general name of chorea. There isoften marked weight loss, possibly in part related to the “exercise”produced by the uncontrollable movements. Eventually the patient ceasesto be able to walk, becomes demented with severe memory loss, andrequires 24 hour nursing care. Death is often caused by pneumonia due toaspiration of food or liquid into the lungs as a result of inability toswallow normally.

[0071] No known treatments are of any substantial value. The abnormalmovements and the psychosis may respond partially to standardanti-schizophrenic drugs, while antidepressants, tranquillizers, andanti-epileptic drugs may help to relieve some symptoms transiently.Nothing stops the inexorable downhill course.

[0072] Because early Huntington's disease may present withschizophrenia-like features, a randomised trial of 96% pure ethyl-EPAwas set up in seven severely disabled patients in the final stages ofHuntington's disease. All required 24 hour nursing care, had severemovement disorders, were irritable and were partially demented. Theywere randomised on a double blind basis to receive 2 g/day ethyl-EPA or2 g/day placebo for 6 months. During the 6 month period, four patientsshowed progressive deterioration while three patients reversed thecourse of the disease and showed improvement with reduced abnormalmovements, reduced emotional lability and irritability and improvedmemory and cognitive function. When the code was broken all fourpatients who deteriorated were found to be on placebo, while all threepatients who improved were found to be taking ethyl-EPA. In four of thepatients, two on ethyl-EPA and two on placebo, the brain degenerationwas assessed at the beginning and end of the study by magnetic resonanceimaging (MRI). MRI allows an accurate assessment of the size of thelateral ventricles, the fluid-filled spaces within the cerebralhemispheres. As Huntington's disease progresses, the lateral ventriclesenlarge indicating loss of brain tissue. In the two patients on placeboover 6 months the ventricles enlarged as expected. In the two patientson ethyl-EPA, the MRI showed a reduction in lateral ventricle sizeindicating an actual reversal of brain tissue loss.

[0073] These dramatic results in patients in the end stage of apreviously untreatable disease caused by abnormal protein accumulationdemonstrate the value of ethyl-EPA in neurodegenerative disorders. Suchdisorders are all associated with membrane damage, oxidative stress andactivation of phospholipases. EPA is able to repair membranes, toinhibit phospholipases and to enhance antioxidant defences. TheHuntington's results therefore support the use of pure ethyl-EPA in theneurological disorders associated with trinucleotide repeats, and thoseassociated with oxidative membrane damage which may sometimes be due toabnormal protein accumulation, including Alzheimer's disease and otherdementias, Lewy body dementia, Parkinson's disease, epilepsies, multiplesclerosis, stroke and head injury and post-stroke and post-injurysyndromes, and diseases of animals and humans due to prion accumulationsuch as kuru, bovine spongiform encepholopathy, Creutzfeldt-Jacobdisease and scrapie.

[0074] Very recently it has been shown that Huntington's disease isassociated with activation of an enzyme called caspase I or interleukinconverting enzyme (ICE). This enzyme is involved in a wide range ofneurodegenerative brain diseases. It generates interleukin-1-beta whichactivates a wide range of pro-inflammatory, cell-damaging actions (V OOna et al, Inhibition of caspase-I slows disease progression in a mousemodel of Huntington's disease. Nature 1999; 399: 263-267). One possibleadditional mechanism of ethyl-EPA action is therefore inhibition ofcaspase-I.

[0075] The present invention has identified ethyl-EPA as being highlyeffective. However, it is likely that any form of highly purified EPAwhich is able to raise EPA levels in the blood is of value inpsychiatric disorders. These EPA compounds will all be of value in thetreatment of psychiatric and neurological disorders when prepared inpure form. It will always be important to keep to the absolute minimumthe presence of related fatty acids, which might interfere with the EPA.The compounds which are known, but which have not previously beenprepared or proposed in such pure forms for use in psychiatric and CNSdisorders are:

[0076] 1. Ethyl-EPA which is widely used in Japan for the treatment ofcardiovascular disorders.

[0077] 2. Lithium-EPA which was previously disclosed in U.S. Pat. No.5,252,333 but which was not then distinguished from any other lithiumHUFA derivative as being of particular value in psychiatric disorders.The value of this derivative lies in the fact that lithium itself is atreatment of choice in bipolar disorder and is also known to havetherapeutic effects in schizophrenia, schizoaffective disorder anddepression. Recently it has been demonstrated that inhibition of PLA2and of the PLC inositol phosphate cycle are important actions oflithium. Since EPA has related actions, the lithium derivative of EPAwill be of particular value.

[0078] 3. Triglycerides, monoglycerides or diglycerides in which morethan 90% and preferably more than 95% of the fatty acids present in themolecule consist of EPA.

[0079] 4. Other esters and compounds capable of delivering fatty acidsto the body in which more than 90% and preferably more than 95% of thefatty acids present are in the form of EPA.

[0080] In each of the above cases there should be less than 5% andpreferably less than 3% of DHA, DPA or AA or other competing fatty acidsindividually. In aggregate there should be less than 10% and preferablyless than 5% of these competing fatty acids.

[0081] These compounds, in 90% and preferably 95% or even purer forms,may all be administered orally via delivery systems known to thoseskilled in the art, including soft and hard gelatin capsules;microcapsules in powder, tableted or capsule form; tablets for the solidcompound, lithium-EPA; or emulsions made with appropriate natural orsynthetic emulsifying agents, including phospholipids or galactolipids.The compounds may also be administered parenterally, either directly, orformulated in various oils or in emulsions or dispersions, using eitherintravenous, intraperitoneal, intramuscular or sub-cutaneous routes.Topical applications using patch technology or vaginal or rectal formsof application are, within the range of the invention.

[0082] The EPA compounds may advantageously in some patients becoadministered with other drugs used in psychiatry and neurology. Suchdrugs may include drugs of the typical neuroleptic class such aschlorpromazine, haloperidol, thioxanthene, sulpiride, droperidol,perphenazine, loxapine, thioridazine, fluphenazine, pericyazine,methotrimeprazine or pimozide among others: clozapine: drugs of theatypical neuroleptic class including olanzapine, risperidone,sertindole, ziprasidone, quetiapine, zotepine and amisulpiride; drugswhich have antidepressant actions including tricyclic and relatedantidepressants, noradrenaline reuptake inhibitors, serotonin reuptakeinhibitors, monoamine oxidase inhibitors and drugs with atypicalantidepressant actions: drugs for sleep disorders, anxiety disorders,panic disorders, social phobias, conduct disorders, personalitydisorders and attentional deficit hyperactivity disorder; drugs for anyform of dementia, including Alzheimer's disease, vascular andmulti-infarct dementias, Lewy body disease and other dementias; drugsfor any form of neurological disease including Parkinson's disease,multiple sclerosis, Huntington's disease and other neurodegenerativedisorders.

[0083] In each of the above cases, the EPA compound and the other drugmay be administered separately, each in their own formulation. They maybe packaged separately or be present in the same overall package.Alternatively, using techniques well known to those skilled in the art,the EPA and other drug may be formulated together, so that a daily doseof EPA of 0.1 g to 10 g per day, and preferably of 0.5 g to 5 g per day,is provided with the normal daily dose of the other drug.

[0084] When supplied alone, the useful daily dose of EPA may be in therange of 0.05 g to 50 g/day, preferably 0.1 g to 10 g/day and verypreferably 0.5 g to 5 g/day.

[0085] It has previously been suggested that omega-3 fatty acids likeEPA may be valuable in the treatment of inflammatory disorders of thejoints, respiratory system, gastro-intestinal system, kidneys, skins,reproductive system and all other organs. However, the importance of thepurity of EPA has not previously been recognised. The invention willtherefore be valuable in these disorders also and the present inventionalso provides pharmaceutical compositions for the treatment of suchinflammatory disorders.

[0086]FIG. 1 shows the pathway by which eicosapentaenoic acid (EPA) issynthesised within the human body from alpha-linolenic acid. FIG. 2shows the other essential fatty acids which are related in structure toEPA. FIG. 3 shows the role of phospholipase A₂ in signal transduction innerve cells. Various neurotransmitters, including dopamine, activatePLA₂ which leads to the formation of a lysophospholipid and a HUFA, bothof which activate the cell. The activation is terminated by a fatty acidcoenzyme A ligase (FACL), particularly FACL-4, which links coenzyme A tothe HUFA, and then by an acyl coenzyme A transferase (ACT) which linksthe HUFA-coenzyme A to a lysophospholipid. In the process coenzyme A isliberated, a stable phospholipid molecule is reformed and the activationprocess is terminated.

[0087] Other EPA derivatives which could be used are the 2-substitutedderivatives of EPA described by N Willumsen, I Vaagenes, H Holmsen and RK Berge (Biochim Biophys Acta 1369: 193-203, 1998). These have theadvantage of having a longer duration of action because they are lessreadily oxidised.

EXAMPLE FORMULATIONS

[0088] In each of the following examples the product is at least 90% andpreferably 95% or more pure. This is very important as other fatty acidswill compete with the EPA for the binding sites and reduce its efficacy.In particular, fatty acids such as DHA, AA, DPA-n-3 will, individually,be present in concentrations of less than 5% and preferably less than3%. The total aggregate of such competing compounds must be less than10% and preferably less than 5%. This degree of purity is also valuablein minimising the volume of material which must be consumed each day, amajor factor in helping compliance in psychiatric patients where lack ofcompliance is a serious problem.

[0089] 1. Capsules made of hard or soft gelatin which contain 250 mg,500 mg, or 1000 mg of ethyl-EPA, triglyceride EPA or other appropriateform of EPA.

[0090] 2. Tablets containing 250 mg, 500 mg or 1000 mg lithium-EPA orhard gelatin capsules containing similar amounts.

[0091] 3. Emulsions, solutions or dispersions in which the lithium-EPA,ethyl-EPA, triglyceride EPA or other appropriate form of EPA areprepared in a palatable liquid form for oral administration.

[0092] 4. Suppositories or pessaries into which 100 mg to 5 g of one ofthe EPA compounds are formulated.

[0093] 5. Intravenous solutions or emulsions containing from 10 mg to500 mg/ml of one of the EPA compounds.

[0094] 5-10. As examples 1-5, but using 2-substituted derivatives ofEPA.

[0095] 11-20. As in 1-10 but in which the EPA compound is formulatedwith the usual dose of any other drug used for the treatment ofpsychiatric or neurological disorders.

[0096] 21-30. As in 1-10 but in which the EPA compound is formulatedwith clozapine.

1. A pharmaceutical preparation comprising EPA in an appropriatelyassimilable form where of all the fatty acids present in the preparationat least 90%, and preferably at least 95%, is in the form of EPA, andwhere less than 5%, and preferably less than 3%, is in the form ofdocosahexaenoic acid (DHA).
 2. A pharmaceutical preparation according toclaim 1 characterised in that among the other fatty acids present thereare less than 5%, and preferably less than 3%, of each of AA or DPA-n-3,individually.
 3. A pharmaceutical preparation according to claim 1 or 2in which the aggregate DHA, AA and/or DPA-n-3 content is less than 10%,of the total fatty acids present and preferably less than 5%.
 4. Apharmaceutical preparation according to any preceding claim in which theEPA is in the form of ethyl-EPA, lithium EPA, mono-, di- or triglycerideEPA or any other ester or salt of EPA, or the free acid form of EPA, orother appropriate bioavailable derivative which raises EPA levels withinthe body.
 5. A pharmaceutical preparation according to any precedingclaim in which the EPA is in the form of a 2-substituted derivative orother derivative which reduces the rate of oxidation without impairingits biological activity.
 6. A pharmaceutical preparation according toany preceding claim for the treatment or prevention of a psychiatric orcentral nervous system disorder.
 7. A pharmaceutical preparationaccording to claim 6 in which the disorder is schizophrenia,schizoaffective disorder or a schizotypal disorder.
 8. A pharmaceuticalpreparation according to claim 6 in which the disorder is depression ormanic-depression (bipolar disorder).
 9. A pharmaceutical preparationaccording to claim 6 in which the disorder is anxiety or panic disorderor social phobia, or a sleep disorder or an attention deficit, conduct,hyperactivity or personality disorder.
 10. A pharmaceutical preparationaccording to claim 6 in which the disorder is Alzheimer's disease oranother dementia, including multi-infarct dementia, Lewy body diseaseand diseases attributable to prion disorders.
 11. A pharmaceuticalpreparation according to claim 6 in which the disorder is Parkinson'sdisease, or other motor system disorder.
 12. A pharmaceuticalpreparation according to claim 6 in which the disorder is multiplesclerosis.
 13. A pharmaceutical preparation according to claim 6 inwhich the disorder is stroke, or the post-stroke syndrome, or headinjury or a post-head injury syndrome.
 14. A pharmaceutical preparationaccording to claim 6 in which the disorder is epilepsy.
 15. Apharmaceutical preparation according to claim 6 in which the disorder isHuntington's disease or any other neurodegenerative disorder, inparticular any disorder due to trinucleotide repeats, includingFriedreich's ataxia, myotonic dystrophy and fragile X syndrome. 16.Formulations for use in psychiatric and neurological disorders in whicha drug which acts primarily on neurotransmitter metabolism or receptorsis prepared for co-administration with a pharmaceutical preparationaccording to any of claims 1-5.
 17. A pharmaceutical formulationcomprising a preparation according to any of claims 1 to 5 together witha drug which acts primarily on neurotransmitter metabolism or receptors.18. A formulation according to claim 16 or 17 in which the drug isclozapine.
 19. A formulation according to claim 16 or 17 in which thedrug is any one of the class of typical or atypical neuroleptics,including chlorpromazine, haloperidol, risperidone, olanzapine,sertindole, ziprasidone, zotepine or amisulpiride.
 20. A pharmaceuticalpreparation according to any of claims 1 to 5 for the treatment ofinflammatory disorders of the joints, respiratory system,gastro-intestinal system, kidneys, skins, reproductive system and allother organs.
 21. Method of treatment of psychiatric and neurologicaldisorders in which a drug which acts primarily on neurotransmittermetabolism or receptors is used in conjunction with a pharmaceuticalpreparation according to any of claims 1-5.
 22. A method of treatmentaccording to claim 21 in which the disorder to be treated isschizophrenia, schizoaffective disorder or a schizotypal disorder.
 23. Amethod of treatment according to claim 21 in which the disorder to betreated is depression or bipolar disorder.
 24. A method of treatmentaccording to claim 21 in which the disorder to be treated is any otherpsychiatric disorder including sleep disorders, anxiety disorders, panicdisorders, social phobias, conduct disorders, personality disorders andattentional and hyperactivity disorders.
 25. A method of treatmentaccording to claim 21 in which the disorder to be treated is any form ofdementia, including Alzheimer's disease, Lewy body disease, vasculardementia and other dementias.
 26. A method of treatment according toclaim 21 in which the disorder to be treated is any form of neurologicaldisease, including Parkinson's disease, Huntington's disease, multiplesclerosis, stroke, epilepsy and other disorders.
 27. A method oftreating or preventing the side effects of a drug used in treatingpsychiatric or neurological disorders by administration of the drug anda pharmaceutical preparation according to any one of claims 1 to 5.